H. Lundbeck A/S and Takeda Pharmaceutical Co. Ltd.'s Lu AA21004, an investigational antidepressant, met the primary endpoint of a Phase III trial in which the compound was being evaluated as a treatment for major depressive disorder (MDD) in elderly patients.

The multinational, double-blind trial included 452 adults aged 65 years or older with recurrent MDD who were randomized to receive eight weeks of treatment with Lu AA21004 5 mg/day, Eli Lilly and Co.'s Cymbalta (duloxetine hydrochloride) 60 mg/d or placebo.

The primary endpoint was the mean change from baseline in the 24-item Hamilton Depression Rating Scale (HAM-D24) total score.

Results showed that the patients who received Lu AA21004 had significantly greater improvement from baseline in HAM-D24 total score as compared with those who received placebo, with a mean between-group difference of 3.3 points.

The proportion of patients who responded to treatment, with response defined as at least a 50 percent decline in HAM-D24 total score, was 53.2 percent in the Lu AA21004 group versus 35.2 percent in the placebo group. Similarly, the proportions of patients who met criteria for remission were 29.2 percent and 19.3 percent, respectively.

In addition, the companies noted, in an analysis of exploratory secondary endpoints, Lu AA21004 was also associated with improvements from baseline in certain measures of cognitive function as compared with placebo.

Withdrawal rates due to adverse events were 5.8 percent and 2.8 percent in the Lu AA21004 and placebo groups, respectively. Nausea was significantly more common with Lu AA21004 (21.8 percent) than with placebo (8.3 percent).

In 2009, Lundbeck and Takeda reported mixed results for the first three trials of the Phase III program for Lu AA21004 in MDD.

The trials compared the drug at doses of 2.5 mg, 5 mg and 10 mg versus placebo. In two of the studies, Lu AA21004 did not differ significantly from placebo. In the third trial, the 5 mg and 10 mg doses differed significantly from placebo, but not in all analyses. Because of these findings, the firms said at the time that they would need to determine the most appropriate dose for the drug, noting that a higher dose might be more efficacious.

An analyst cited by Reuters at the time called the news "very negative" and said the results raised questions about whether the compound would ever reach the market.

Lundbeck and Takeda are investigating Lu AA21004 as a multimodal antidepressant. According to the two firms, evidence suggests that the compound modulates neuronal firing and neurotransmitter release in multiple systems, leading to enhanced levels of serotonin, noradrenaline, dopamine, acetylcholine and histamine in specific areas of the brain.

The companies formed a strategic alliance in 2007 for the exclusive co-development and co-commercialization of several compounds in Lundbeck's pipeline for the treatment of mood and anxiety disorders.